Analysis of alphaVbeta8 Integrin In Gliomagenesis

αVβ8 整合素在胶质瘤发生中的分析

• 批准号: 7662254
• 负责人: Joseph H McCarty
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662254
• 关键词: Ablation; Address; Adult; Animals; Astrocytes; Blood Vessels; Brain; Brain Neoplasms; CD34 gene; Cell Adhesion; Cell Adhesion Molecules; Cell surface; Cells; Central Nervous System Diseases; Collaborations; Communication; Data; Development; Disease; ECM receptor; Edema; Endothelial Cells; Event; Extracellular Matrix; Extracellular Matrix Proteins; Family; Gene Expression; Genes; Genetic; Genetically Engineered Mouse; Glioblastoma; Glioma; Gliomagenesis; Goals; Growth; Hemorrhage; Homeostasis; Human; Implant; Integrins; Intracranial Neoplasms; Knockout Mice; Lead; Lesion; Link; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Modeling; Molecular; Molecular Genetics; Mus; Mutant Strains Mice; Neuraxis; Neuroglia; Neurons; Neurosurgeon; Non-Malignant; Oncogenes; Pathogenesis; Pathology; Pattern; Perivascular Neoplasm; Phenotype; Play; Population; Primary Brain Neoplasms; Regulation; Resected; Role; Signal Pathway; Staging; Stem cells; Testing; Transgenic Mice; Tumor Stem Cells; Tumor Tissue; United States; University of Texas M D Anderson Cancer Center; Virus; Work; adhesion receptor; angiogenesis; base; cell growth; human tissue; in vivo; integrin alphavbeta8; member; mouse model; mutant; neoplastic cell; nerve stem cell; nervous system development; new therapeutic target; novel therapeutics; prevent; public health relevance; research study; spatial relationship; tool; tumor; tumor growth

DESCRIPTION (provided by applicant): Among the billions of neurons and glia in the vertebrate central nervous system (CNS) is a rich milieu of extracellular matrix (ECM) proteins. Most CNS cells interact with ECM components via members of the integrin family of cell surface adhesion receptors. Precise regulation of integrin-ECM communication is necessary for normal CNS development and homeostasis, and abnormal regulation of these events can contribute to the pathogenesis of various CNS diseases, including cancer. In this project we will determine how av¿8 integrin contributes to the pathogenesis of the deadly brain cancer, glioblastoma multiforme (GBM). GBMs and other high-grade gliomas develop severe blood vessel pathologies, including abnormal angiogenesis and associated edema and hemorrhage. Our working hypothesis is that reduced av¿8 integrin expression and function in tumor-initiating cells contributes to vascular pathologies in high-grade gliomas. The rationale for pursuing these studies is based on the following experimental data: (i) av¿8 integrin is expressed in neural stem cells and astroglia, which are presumptive cells of origin for glioma; (ii) genetic ablation of the murine av or ¿8 integrin genes in mouse neural stem cells and astroglia results in brain-specific vascular phenotypes that are similar to pathologies observed in high-grade gliomas; (iii) transformed astroglia that lack av¿8 integrin generate intracranial tumors with vascular abnormalities similar to those found in high-grade gliomas; and (iv) tumor stem cells primarily contribute to vascular pathologies in gliomas, and av¿8 integrin expression defines sub-populations of human glioma stem cells, with nearly 50% of GBM stem cells lacking av¿8 integrin expression. In this project we propose experiments to study functions for av¿8 integrin in brain tumor-initiating cells during gliomagenesis. To accomplish these goals we will use a unique set of molecular genetic tools, consisting of av and ¿8 integrin mutant mice, as well as cells purified from mutant animals. Additionally, we will study the expression and function of av¿8 integrin in resected human glioma tissues and human glioma stem cells. We propose the following Specific Aims: (1) We will determine the functional roles for av¿8 integrin in tumor-induced angiogenesis using orthotopic and genetically engineered mouse models of glioma, and (2) We will determine the functional roles for av¿8 integrin in vascular pathologies that typify human malignant gliomas. Collectively, these experiments will elucidate the functional role for av¿8 integrin during gliomagenesis, particularly related to tumor-induced vascular pathologies. This work may eventually lead to new therapeutic strategies for treating or preventing the progression of high-grade gliomas in humans. PUBLIC HEALTH RELEVANCE: Gliomas afflict approximately 20,000 people within the United States each year. They represent the most common type of primary brain tumors, and, in their advanced stages, they are one of the deadliest forms of cancer. Understanding the basic cellular and molecular events that contribute to glioma growth, angiogenesis, and invasiveness may lead to new therapeutic strategies to treat or prevent the pathogenesis of this insidious disease. In this project we will study how cell adhesion molecules, known as integrins, regulate the onset and progression of gliomas in mice and humans. These results may identify new therapeutic targets to treat or prevent the development of gliomas in humans.

描述（由应用提供）：在脊椎动物中枢神经系统（CNS）中的数十亿个神经元和神经胶质中，是细胞外基质（ECM）蛋白质的丰富环境。大多数CNS细胞通过细胞表面粘合受体的整合素家族的成员与ECM成分相互作用。整联蛋白-ECM通信的精确调节对于正常的中枢神经系统发育和稳态是必要的，这些事件的异常调节可能有助于包括癌症在内的各种CNS疾病的发病机理。在这个项目中，我们将确定AV¿8整联蛋白如何促进致命脑癌的发病机理多形胶质母细胞瘤（GBM）。 GBM和其他高级神经胶质瘤会产生严重的血管病理，包括异常血管生成以及相关的水肿和出血。我们的工作假设是，在肿瘤发射细胞中降低了AV¿8整联蛋白的表达和功能，导致高级神经胶质瘤的血管病理。追求这些研究的基本原理是基于以下实验数据：（i）在神经干细胞和星形胶质细胞中表达的整合素，它们是神经胶质瘤的原始细胞； （ii）小鼠神经元干细胞和星形胶质细胞中鼠AV或8整合素基因的遗传消融导致脑特异性血管表型，这些血管表型类似于在高级神经胶质瘤中观察到的病理学； （iii）变化的缺乏AV¿8整联蛋白的星形胶质素会产生颅内肿瘤，其血管异常类似于高级神经胶质瘤中的肿瘤。 （iv）肿瘤干细胞主要有助于神经胶质瘤中的血管病理，而AV？8整合素表达定义人神经胶质瘤干细胞的亚群，几乎50％的GBM干细胞缺乏AV¿8整合素表达。在这个项目中，我们提出了实验，以研究神经胶质作用期间脑肿瘤诱导细胞中AV¿8整联蛋白的功能。为了实现这些目标，我们将使用一组独特的分子遗传工具，这些遗传工具由AV和8整联蛋白突变小鼠组成，以及从突变动物纯化的细胞。此外，我们将研究Av¿8整合素在切除的人神经胶质瘤组织和人神经胶质瘤干细胞中的表达和功能。我们提出以下具体目的：（1）我们将使用原位和基因工程的小鼠模型在肿瘤诱导的血管生成中确定AV¿8整合素的功能作用。总的来说，这些实验将在神经胶质作用期间阐明AV¿8整联蛋白的功能作用，特别是与肿瘤诱导的血管病理相关。这项工作最终可能导致新的治疗策略，以治疗或防止人类高级神经胶质瘤的发展。公共卫生相关性：每年在美国大约有20,000人的神经胶质瘤。它们代表了原发性脑肿瘤的最常见类型，在其晚期阶段，它们是最致命的癌症之一。了解有助于神经胶质瘤生长，血管生成和侵入性的基本细胞和分子事件可能会导致新的治疗策略来治疗或防止这种阴险疾病的发病机理。在这个项目中，我们将研究细胞粘附分子（称为整联蛋白）如何调节小鼠和人类神经胶质瘤的发作和进展。这些结果可能会确定新的治疗靶标，以治疗或防止人类神经胶质瘤的发展。